Project Summary Enterotoxigenic Escherichia coli (ETEC) are the most common cause of diarrhea, afflicting millions of children in the developing world. However, the true burden of ETEC in young children and the role of acquired immunity remains poorly understood. Accurate estimates in different geographic regions will highlight the public health importance of a vaccine, and these data are critically important to reduce the burden and to facilitate vaccine development. A significant challenge to successful vaccine development is our poor understanding of the immune responses that correlate best with protection against ETEC illness. A better understanding of the interplay between local and serum responses to various ETEC strains in non-immune and immune subjects is needed since these data will provide important immunological benchmarks for the evaluation of ETEC vaccines and immunization regimens in the future. We propose to add studies of ETEC to an already NIH-funded newborn cohort study of norovirus and sapovirus infection in a peri-urban Lima community, where we have conducted child cohort studies for more than 20 years. By leveraging this study, we can gain information about ETEC at a fraction of the cost were it a stand-alone study. To facilitate this proposed work, we are collaborating with a JHU ETEC research team, which provides access to expertise and state-of-the-art techniques to evaluate ETEC disease and naturally-acquired immunity. As in the parent study, we will follow the infants through a longitudinal community cohort to fully understand the natural immunity to a disease that infects young infants multiple times early in life. We will address the knowledge gap of ETEC epidemiology and immune response in young children by addressing issues key to effective vaccine design and deployment: we will quantify the genotype-specific ETEC incidence and morbidity, and we will evaluate acquisition of protective immunity by correlating host blood group antigen, secretor status, and ETEC antigen specific antibodies in serum, fecal matter, and saliva with ETEC disease, infection, and shedding. Specific Aim 1. Characterize the epidemiology of ETEC in Peruvian children by conducting a longitudinal cohort study from birth to age 3 years including systematic collection of data and specimens. Specific Aim 2. Evaluate acquired protective immunity to ETEC in a setting of frequent exposure in a subset of cohort children.